Factor Xa Inhibitors Research Articles

Physiologically based pharmacokinetic modeling of apixaban to predict exposure in populations with hepatic and renal impairment and elderly populations

BackgroundApixaban is a factor Xa inhibitor with a limited therapeutic index that belongs to the family of oral direct anticoagulants. The pharmacokinetic (PK) behavior of apixaban may be altered in elderly populations and populations with renal or hepatic impairment, necessitating dosage adjustments.MethodsThis study was conducted to examine how the physiologically based pharmacokinetic (PBPK) model describes the PKs of apixaban in adult and elderly populations and to determine the PKs of apixaban in elderly populations with renal and hepatic impairment. After PBPK models were constructed using the reported physicochemical properties of apixaban and clinical data, they were validated using data from clinical studies involving various dose ranges. Comparing predicted and observed blood concentration data and PK parameters was utilized to evaluate the model’s fit performance.ResultsDoses should be reduced to approximately 70% of the healthy adult population for the healthy elderly population to achieve the same PK exposure; approximately 88%, 71%, and 89% of that for the elderly populations with mild, moderate, and severe renal impairment, respectively; and approximately 96%, 81%, and 58% of that for the Child Pugh-A, Child Pugh-B, and Child Pugh-C hepatic impairment elderly populations, respectively to achieve the same PK exposure.ConclusionThe findings indicate that the renal and hepatic function might be considered for apixaban therapy in Chinese elderly patients and the PBPK model can be used to optimize dosage regimens for specific populations.

Development of a Rapid Qualitative Screen for Anticoagulant Presence.

Direct oral anticoagulants (DOACs) and fondaparinux with stable pharmacokinetics are commonly used anticoagulants for outpatient care. Due to the lack of monitoring requirements, drug-specific assays are not available in most hospital laboratories, but drug levels are needed in some urgent/emergency situations. This study describes the development of a qualitative screen for the presence of DOAC or fondaparinux using coagulation tests found in most laboratories. The DOAC screen is composed of a heparin anti-Xa activity assay and thrombin time (TT) assay. The STA®-Liquid-Anti-Xa assay calibrated with Stago Multi Hep® and STA®-TT were run on STA-R Max® analyzers. The anti-Xa activity and TT assays were repeated 5 times in samples of commercially available calibrators and controls for each drug: fondaparinux, dabigatran, rivaroxaban, apixaban, and edoxaban. Statistical analysis and correlations were performed for anti-Xa activity and TT results for each drug and pooled normal plasma. A significant correlation was found between heparin-calibrated anti-Xa levels and fondaparinux, rivaroxaban, apixiban, and edoxaban (r2 = 0.99-1.0). Dabigatran showed a strong linear correlation (r2 = 0.99) with TT. Anti-Xa levels >0.3 IU/mL and TT >25 seconds were determined as cutoffs at our lab for the detection of clinically relevant drug levels of factor Xa inhibitor and direct thrombin inhibitor, respectively. Our study demonstrates that commonly available heparin anti-Xa activity and TT assays can be used to qualitatively detect DOACs and fondaparinux and provides a method to establish a qualitative interpretation.

Venous thromboembolism, chronic liver disease and anticoagulant choice: effectiveness and safety of direct oral anticoagulants versus warfarin

BackgroundLittle to no data exist to guide treatment decision in patients with venous thromboembolism (VTE) and chronic liver disease. ObjectivesTo assess the effectiveness and safety of direct oral anticoagulants (DOACs)—individually and as a class—vs warfarin and between 2 DOACs in patients with acute VTE and chronic liver disease. MethodsWe conducted a retrospective, US claims–based, propensity score–matched cohort study in adults with acute VTE and chronic liver disease who had newly initiated oral anticoagulants between 2011 and 2017. The primary outcome was a composite of hospitalization for recurrent VTE and hospitalization for major bleeding. ResultsThe cohorts included 2361 DOAC-warfarin, 895 apixaban-warfarin, 2161 rivaroxaban-warfarin, and 895 apixaban-rivaroxaban matched pairs. Lower risk of the primary outcome was seen with DOACs (hazard ratio [HR], 0.72; 95% CI, 0.61-0.85), apixaban (HR, 0.48; 95% CI, 0.35-0.66) or rivaroxaban (HR, 0.73; 95% CI, 0.61-0.88) vs warfarin but not apixaban-rivaroxaban (HR, 0.68; 95% CI, 0.43-1.08). The HRs of hospitalization for major bleeding were 0.69 (95% CI, 0.57-0.84) for DOAC-warfarin, 0.43 (95% CI, 0.30-0.63) for apixaban-warfarin, 0.72 (95% CI, 0.58-0.89) for rivaroxaban-warfarin, and 0.60 (95% CI, 0.35-1.06) for apixaban-rivaroxaban. Recurrent VTE risk was lower with apixaban (HR, 0.47; 95% CI, 0.26-0.86), but not DOACs (HR, 0.81; 95% CI, 0.59-1.12) or rivaroxaban vs warfarin (HR, 0.81; 95% CI, 0.57-1.14) or apixaban-rivaroxaban (HR, 0.92; 95% CI, 0.42-2.02). ConclusionWhile the magnitude of clinical benefit varied across individual DOACs, in adults with acute VTE and chronic liver disease, oral factor Xa inhibitors (as a class or individually) were associated with lower risk of recurrent VTE and major bleeding.

Performance of a direct oral anticoagulant removal reagent, DOAC-StopTM, for lupus anticoagulant testing

Abstract Objective Routine use of direct factor Xa inhibitor (direct oral anticoagulant; DOAC) therapy necessitates a modified lupus anticoagulant (LAC) testing method for this population. To remove interfering DOACs in specimens, DOAC-StopTM treatment was used on LAC specimens to assess for antiphospholipid syndrome (APS) without altering patient’s anticoagulation treatment. Methods DOAC-StopTM was evaluated with our LAC testing panel with dilute Russell viper venom time (dRVVT), and Silica Clotting Time (SCT) assays, both of which activate coagulation. DOAC-StopTM beads were used for pretreatment by addition and rocking for 5 minutes, followed by 5000 rpm centrifugation for 5-minutes. Treated plasma supernatant was used for a screen, confirm (addition of phospholipid), 50:50 mix (addition of reagent plasma with coagulation factors), and confirm 50:50 mix phases of testing. The Total Ratio (TR; ratio between screen and confirm ratios relative to mean of normal ranges) was calculated and used per the package insert for interpretation. Implementation data was assessed for interpretation differences between groups with and without DOAC-StopTM treatment. Results Patients being tested for APS by LAC assay with and without DOAC therapy were included. DOACs included apixaban or rivaroxaban. Primary interpretations included no evidence of a LAC (NELAC), evidence of LAC, and results more consistent with coagulation factor deficiency. The effectiveness of DOAC removal was established by spiking NELAC samples with apixaban and treating with DOAC-StopTM, resulting in removal of anti-factor Xa activity. An apixaban spiking study with NELAC and LAC patient specimens with LAC testing before and after DOAC-StopTM treatment demonstrated unchanged interpretations. In a test modification study, Rivaroxaban resulted in positive dRVVT interpretations in nine of ten patients. All but one became negative after DOAC-StopTM treatment. Two SCT interpretations became positive after treatment. Apixaban resulted in two positive dRVVT interpretation in nine patients, one of which became negative after DOAC-StopTM treatment. SCT interpretations remained unchanged. Review of implementation data (n=78) with nine patients on DOACs having DOAC-StopTM treatment demonstrated similar patterns of test interpretation. Interpretations included: “no evidence of a LAC” in 53% (n=41) without and 55% (n=5) with DOAC-StopTM, “Does not meet criteria” in 17% (n=13) without and 11% (n=1) with DOAC-StopTM, “Evidence of a LAC” in 21% (n=16) without and 33% (n=3) with DOAC-StopTM. The remaining eight patients without DOAC-StopTM treatment had interpretations including factor deficiency, warfarin effect, equivocal, or concerning for interference. Conclusion Patients on DOACs benefit from DOAC-StopTM –enable LAC testing for APS assessment. Data analysis demonstrates that DOAC-StopTM effectively removes DOAC interference in the majority of tests with similar rates of major interpretation categories. LAC testing and interpretation for patients on DOAC therapy shows promise with novel approaches and reagents such as DOAC-StopTM, though interpretative challenges with false-positives and false-negatives continue.

Updated Protocol for the Phase 3, Randomized, Double-Blinded Lex-210 Study of Four-Factor Prothrombin Complex Concentrate in Patients with Acute Major Bleeding on Factor Xa Inhibitor Therapy

Background and Significance: Despite significantly reduced risk of intracranial hemorrhage compared with vitamin K antagonists, direct oral anticoagulant therapy with factor Xa inhibitors (FXaI) is associated with similar incidences of other major bleeds. Although hemostatic agents such as prothrombin complex concentrates (PCCs) are often used (off-label), the efficacy and safety of PCCs for managing FXaI-related bleeding requires further investigation. This study aims to evaluate superior hemostatic efficacy of high-dose vs low-dose four-factor (4F) PCC (Octaplex®; Octapharma) in adults with FXaI-related major bleeding. Study Design and Methods: LEX-210 (NCT04867837) is a Phase 3, multicenter, prospective, randomized, double-blinded, group-sequential, parallel-group, adaptive design study. Significant modifications have recently been made to the study design. Patients aged ≥18 years with acute major bleeding (e.g., gastrointestinal, intracranial) and baseline anti-factor Xa activity of ≥100 ng/mL are eligible. To increase rate of recruiting suitable patients into the study, the eligibility criteria have been optimized. For inclusion (full criteria in Table 1), baseline anti-factor Xa activity of ≥100 ng/mL may be either confirmed by locally available tests (including retrospectively by the central laboratory) or suspected by the investigator and later confirmed by the central lab. Prospective written informed consent will be obtained from all patients or patients' legally authorized representative prior to enrolment. If this is not possible, in countries outside the US where it is permitted under local regulations or approved by local ethics committees, deferred consent procedures may be applied. Key exclusion criteria (Table 2) include acute trauma for which FXaI reversal alone would not be expected to control bleeding, and thromboembolic events in the last 3 months. In addition, hypersensitivity to heparin and platelet inhibitors are specified. Patients will be excluded if they score <7 on the Glasgow Coma Scale (with allowances for intubation), or have expected survival of <24 hours. While patients scheduled for surgery in <12 hours are excluded, minor surgeries and invasive procedures for diagnostic or therapeutic reasons are allowed, or if intended to address a second (non-index) bleeding event. Patients will be randomized 1:1 to 50 or 15 IU/kg 4F-PCC. The primary objective is to demonstrate superior hemostatic efficacy of the higher dose in patients with major bleeding associated with FXaI. Hemostatic efficacy through 24 hours after receipt of 4F-PCC will be evaluated by an independent data monitoring and endpoint adjudication committee using objective criteria, with a binary outcome of effective or ineffective. Secondary endpoints include change in endogenous thrombin potential (baseline to 1 hour after 4F-PCC), 30-day rates of thromboembolic events, and all-cause mortality. The study is conducted in accordance with the ethical principles laid down in the Declaration of Helsinki The proportion of patients with an effective outcome will be compared between groups using a one-sided z-test. The primary statistical model will be adjusted for the baseline anti-factor Xa activity as determined retrospectively by the central laboratory. A logistic regression model for the success rate using treatment group (dose level) and the anti-factor Xa activity as fixed effects will be used to determine the one-sided z-statistic. LEX-210 launched in Q4 2021 and will be performed across ~60 sites in North America and the European Continent. Target enrollment is ~260 patients, assuming a 30% dropout rate. So far, 26 sites in the US, Italy, Germany, and Spain have been initiated, with 5 patients enrolled. Study completion is anticipated in Q3 2024.

Quality of Oral Anticoagulation with Vitamin K Antagonists and Direct Oral Anticoagulants in ‘real-World’ Patients: Lessons from a Five Years Audit Study

Background: Even with the introduction of direct oral anticoagulants (DOACs), anticoagulation clinics (ACs) stand with a key role in monitoring. Indeed, routine evaluation by health care professionals is recommended as it is with vitamin K antagonists (VKA) with adjustments in practices of anticoagulation management services. Quality of oral anticoagulation (QOA) is associated to better clinical outcomes in those patients with indications for such therapy. It is well established that patients receiving VKA therapy, maintenance of an international normalized ratio (INR) in the therapeutic range is essential for treatment efficacy and safety. It has been reported that ACs should aim for a time in therapeutic range (TTR) between 70-80% to optimize benefit and minimize the risk of adverse events. So far, QOA for DOACs is not fully established. Aim: Since few clinical data are available considering the new era of ACs, this study aims to describe actual trends and QOA of an AC at a large academic medical hospital. Methodology: We retrospectively analyzed 23275 appointments of 5 consecutive years (May 2018 to May 2023), corresponding to 930 patients that are regularly followed up at an outpatient AC of a central hospital under anticoagulation for at least 8 weeks. TTR (≥70%) determined by Rosendaal method was used for patients under AVK and for those individuals in DOACs, QOA was considered the presence of therapeutic plasma levels of the drugs after the European Heart Rhythm Association 2021 in, at least, one determination. Patients were divided according to target INR in 3 groups: Group 1 with target INR 2-3, including 809 patients mean age 65±18 years (mean±SD), majority (36.6%) with atrial fibrillation (AF); Group 2 with target INR 2.5-3.5, including 92 patients with mean age 70±11 years, majority (85.9%) with mechanical heart valves; Group 3 with target INR 3-4, including 29 patients with mean age 63±15 years, majority (55.5%) with antiphospholipid syndrome. Seventy patients were under DOACs (apixaban in 74.3%), with mean age of 71±17 years, majority (62.9%) with non-valvular AF, were included in Group 1 and all individuals were under direct inhibitors of factor Xa. Descriptive statistics (mean, standard deviation, minimum, maximum, chi-square), inferential statistics (t-test, A-Nova and effect sizes) tests were performed. Results: The 930 patient population, 52.2% female, mean age of 65±18 years and 87% in Group 1, showed a mortality of 17%. The mean recall interval between appointments was superior to 90 days in 94% of the population. The individuals who died in comparison with the survivors showed higher frequency of AF (54.1%) [ χ 2= 47.099; p<.001; φ=.225], were from Group 1 (93%) [ χ 2= 6.641; p=.036; φ=.085], male (59.2%) [ χ 2= 10.103; p=.001; φ=-.104] and older [76±12 vs .63±18 years (p<.001), respectively]. No differences were noticed in mortality between AVK and DOACs [ χ 2= 1.828; p=.401; φ=-.044], even DOAC patients being older than AVK patients (71±17 vs 65±17; p=.005), respectively. QOA associated with mortality being the individuals who died with higher frequency of no QOA (21.9% vs 13.9%) [ χ 2= 8.126; p=.004; φ=-.101] respectively. The individuals on AVK from Group 1 corresponding to 86% of total population showed a mean TTR of 76%, patients from Group 2 had a TTR of 72% and patients in Group 3 had TTR of 55%. From the individuals under DOACs, only 30% had at least one determination of plasma levels of the drug and all but one showed therapeutic levels. Comparatively with our previous studies related to the periods of 2006-2012 and 2012-2018, we noticed a significant decrease in patient population / appointments size (2087/ 61988) (1587/ 37931),(p <.001) with an increase of TTR in Group 1 (1927/1430 patients) (83% /72%) and Group 2 (120/125 patients) (74% / 69%) but a TTR decrease in Group 3 (40 / 32 patients) (54% / 60%) (p <.001). respectively. Mortality in the 2012- 2018 period was 18%. Conclusions and Discussion: The trends of decreasing the number of anticoagulated patients at our AC with an overall good quality of monitoring but with a low percentage of individuals under DOACs suggests that the majority of anticoagulated population is on these drugs without routine follow up in opposition to the recent recommendations. Our study underlines the importance of the quality of anticoagulation monitoring on mortality that was no different from the previous years before SARS-CoV- 2 pandemic nor between AVK and DOACs.

Risk Factors Associated with Anticoagulant-Related Bleeding in Patients with Cancer-Associated Thrombosis

Background: Patients with cancer-associated thrombosis (CAT) have a high risk of recurrent venous thromboembolism as well as anticoagulant-related major bleeding. Thus, initiation and maintenance of anticoagulant therapy requires careful consideration of the risk versus benefit of therapy. Prior literature demonstrates that existing bleeding risk models have mediocre to moderate predictive performance for anticoagulant-related bleeding in patients with cancer. Patients with cancer have unique risk factors for bleeding that are absent in many of these models. Thus, we aimed to evaluate the association candidate traditional and cancer-specific risk factors with anticoagulant-related bleeding in a large cohort of patients with CAT. Methods : Using a nationwide cohort of US Veterans, we identified patients diagnosed with CAT with a new prescription for anticoagulant therapy between 2012 and 2020. Eligible anticoagulant therapy included a prescription for at least 30 days of: direct oral anticoagulants (DOACs), direct selective factor Xa inhibitors, low molecular-weight-heparin (LMWH), or vitamin K antagonists (VKA). Patients with outpatient prescriptions for anticoagulation within the six months preceding CAT were excluded. We further identified a subgroup of patients on chemotherapy around the time of CAT diagnosis, chemotherapy cohort. Using the methods of Fine and Gray, we assessed the association between candidate risk factors and clinically significant anticoagulant-related bleeding using competing risk analyses to account for the competing risk of death. Anticoagulant related bleeding was identified using previously validated international classification of disease (ICD) coding, with position dependent on site of bleed. Results : We identified a cohort of 11,731 patients with CAT, of whom 4,298 patients received anti-cancer systemic therapy within 6 months before to 12 months after CAT diagnosis. The most common malignancies represented in the full cohort included lung (23%), gastrointestinal (14%), and prostate (11%). Most patients received anticoagulant therapy with LMWH (47.7%), followed by DOACs (26.8%), VKAs (24.5%), and fondaparinux (1%). When assessing anticoagulant trends over time, DOACs were the treatment of choice by 2018 with 45.3% of patients receiving initial therapy with a DOAC and further increased to 78.1% by 2020. The 6-month and 12-month cumulative incidence of bleeding in the full cohort was 7% (CI 6.5-7.5) and 9.5% (CI 8.9-10.1), respectively. In the chemotherapy cohort, 6-month and 12-month cumulative incidence of bleeding was 7.9% (CI 7.1-8.8) and 12% (CI 10.8-13.2). In both the chemotherapy and full cohorts, the most frequent sites of clinically significant bleeding included gastrointestinal (GI) tract (57.2%, 54.5%), genitourinary (GU) tract (excluding microscopic hematuria) (20.2%, 21.2%), and intracranial hemorrhage (10.4%, 11.4%) respectively. Of the traditional candidate variables assessed in the full cohort, history of bleeding, estimated glomerular filtration rate (eGFR), uncontrolled hypertension, predisposition to falling, history of ischemic stroke, alcohol abuse, anemia (defines as hemoglobin < 13g/dL in men and < 12 g/dL in women), and liver disease had the highest association with anticoagulant-related bleeding. In addition, use of chemotherapy was associated with an increased risk of bleeding. Findings were similar in the chemotherapy cohort, history of ischemic stroke, alcohol abuse, and anemia were no longer associated with bleeding risk. Of cancer specific candidate variables, GI cancer, GU cancer and metastatic cancer was most predictive. Full results of the analyses are in Table 1 for both the full and chemotherapy cohorts. Conclusions : In this study, many candidate variables in available risk prediction models for anticoagulant-related bleeding were not associated with bleeding risk. This may explain the performance of these models in patients with cancer on anticoagulant therapy. We identified cancer-specific candidate variables that were associated with risk of anticoagulant-related bleeding. Incorporation of these cancer-specific variables into available models could improve predictive performance.

Efficacy and Safety of Direct Oral Anticoagulants for Stroke Prevention in Older Patients With Atrial Fibrillation: A Network Meta-Analysis of Randomized Controlled Trials.

Although older patients with atrial fibrillation are at heightened risk of thromboembolic and bleeding events, their optimal treatment choice remains uncertain. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched the PubMed, EMBASE, and Cochrane databases for randomized controlled trials that compared thromboembolic or bleeding outcomes between a direct oral anticoagulant (DOAC) and a vitamin K antagonist (VKA) and reported outcomes for patients aged ≥75 years with atrial fibrillation. The efficacy outcome was the composite of stroke and systemic embolism. Safety outcomes included major bleeding, any clinically relevant bleeding, and intracranial hemorrhage. Each DOAC and VKA was compared pairwise in a network meta-analysis. High- and low-dose regimens and factor IIa and Xa inhibitors were also compared. Seven randomized controlled trials were included in the analysis. Stroke and systemic embolism risks did not differ significantly among DOACs. There were no significant differences in major bleeding between each DOAC and VKA. Intracranial hemorrhage risk was significantly lower with dabigatran, apixaban, and edoxaban than with VKA and rivaroxaban, which had similar risks. High-dose regimens led to lower risks of stroke or systemic embolism compared with VKA and low-dose regimens, with both doses having similar bleeding risks. In patients aged ≥75 years with atrial fibrillation, DOACs were associated with fewer thromboembolic events compared with VKA, whereas dabigatran, apixaban, and edoxaban were associated with lower risks of intracranial hemorrhage compared with VKA and rivaroxaban. URL: www.crd.york.ac.uk/prospero/. Unique identifier: CRD42022329557.

Phenotypic Heterogeneity and Outcomes in Severe Protein C Deficiency: A Report of Two Patients

Background: Protein C is a zymogen that suppresses the coagulation cascade through proteolysis of factors V and VIII, and therefore its deficiency is a risk factor for thromboembolic events 1. There are two main subtypes of protein C deficiency. In type I protein C deficiency, both protein C antigen and activity levels are decreased, resulting in low protein C or inadequate protein lifespan 2. In type II deficiency, the activity level is lower than the antigen level due to abnormal protein activity 2. Inherited protein C deficiency is caused by either compound heterozygous or homozygous pathogenic variants in the POMC gene. Objective: To describe the clinical presentation and outcomes of 2 severe protein C deficiency cases. Patient #1 is an 8-year-old male with history of neonatal stroke, dense left hemiplegia, and cerebral palsy, who underwent whole exome sequencing due to MRI findings (Figure 1a). This identified an apparently homozygous variant in POMC, c.1154T>C (p. Met385Thr)in exon 9. Both parents were confirmed to be heterozygous carriers. The patient was found to have a normal antigen of 62% and a severely low activity of <10%, suggesting a diagnosis of type II protein C deficiency. He is being considered for extended anticoagulation with a direct Xa or IIa inhibitor or a vitamin K antagonist. Patient #2 was born at 34 weeks and presented immediately following birth with a large occlusive thrombus in the ascending to proximal aorta as well as left ventricular dysfunction and mitral regurgitation (Figure 1b). She was not a candidate for thrombectomy or catheter-directed tissue plasminogen activator (TPA) due to her age and procedural risks. She was given systemic TPA due to severe end organ dysfunction followed by unfractionated heparin (UFH). Due to neurological changes and intracranial hemorrhage (ICH), TPA and UFH were discontinued. Fresh frozen plasma and protein C concentrate were administered and UFH was resumed. Due to worsening ICH, UFH was again stopped, and she developed a left ventricular thrombus, impairing her systemic circulation. Her clinical status worsened, and she became unresponsive to resuscitation efforts, and passed away on DOL 16. Testing identified a protein C antigen and activity level of 10% and <15% respectively. This patient was found to have 2 variants in the PROC gene, c.30C>T (p. Phe10Phe), which is a variant of uncertain significance, and c.1019C>T (p. Thr340Met), which is known to be pathogenic. Discussion: Both cases highlight uncommon presentations of severe protein C deficiency without purpura fulminans. Management of severe protein C deficiency consists of protein C replacement or long-term anticoagulation with warfarin as the standard of care 3,4. However protein C concentrate is costly, requires intravenous access, and can cause hypersensitivity reactions and hemorrhage. Long-term warfarin treatment is burdensome for families, requiring frequent laboratory monitoring with variable time in the therapeutic range. The only curative option for protein C deficiency is liver transplantation, which has additional risks and has rarely been reported in the literature 3,4. Conclusions: These cases illustrate the phenotypic heterogeneity of inherited severe protein C deficiency and demonstrate the challenges of clinical management in this patient population. The International Society on Thrombosis and Haemostasis initiated a severe protein C deficiency registry in 2013 which will standardize and improve treatment of this rare condition.

Decrease of prothrombin level during thrombolysis in acute myocardium infarction.

Previously, the direct interactions of Bβ26-42 fibrin residues with prothrombin were demonstrated. It was also shown that forming prothrombin complexes with E- or DDE-fragments causes non-enzymatic prothrombin activation. The direct measuring of the prothrombin level in the blood plasma of patients with acute myocardial infarction (AMI) allowed us to find a situation where such an activation can occur in vivo. Blood coagulation parameters in the blood plasma of patients with AMI were measured at 2 hours, three days, and seven days after the thrombolysis by streptokinase accompanied with intravenous administration of anticoagulants: unfractionated high molecular weight heparin (HMWH) and low-molecular-weight heparin (LMWH). The prothrombin level in the blood plasma of patients with AMI was normal before thrombolytic therapy and substantially decreased after streptokinase administration. This effect was prominent in the case of concomitant anticoagulant therapy with LMWH and was not observed when HMWH was applied. It can be explained by the fact that LMWH preferentially inhibits factor Xa, while the HMWH is an effective inhibitor of both factor Xa and thrombin. This observation suggested that the prothrombin level decrease was caused by the thrombin-like activity and possible autolysis of prothrombin by thrombin. Also, thrombolytic therapy with streptokinase caused the accumulation of fibrin degradation products (FDPs), some of which were able to bind prothrombin. The dramatic decrease of prothrombin level in the blood plasma of patients with AMI during thrombolysis allowed us to conclude the non-enzymatic prothrombin activation with the following autolysis of prothrombin that contributes to the pathology.

Cancer-Associated Venous Thromboembolism-Diagnostic and Therapeutic Considerations: An Update Based on the Revised AWMF S2k Guideline.

Patients with cancer are prone to develop venous thromboembolism (VTE) with negative impact on quality of life, morbidity, and mortality. Treatment of established VTE is often complex in patients with cancer. Treatment of cancer-associated VTE (CAT) basically comprises initial and maintenance treatment, for 3 to 6 months, secondary preventions, and treatment in special situations. Therapeutic anticoagulation is the treatment of choice in CAT. In addition to the efficacy and safety of low-molecular-weight heparin (LMWH) that had been recommended for decades, direct oral anti-factor Xa inhibitors, a subgroup of direct oral anticoagulants (DOACs), demonstrated their advantages along with the accompanying concerns in several randomized controlled treatment trials of CAT. The latest guidelines, such as the German AWMF-S2k Guideline "Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism," agree with each other on most aspects with respect to the treatment of CAT. Encompassing recent clinical studies, and meta-analyses, as well as the focus on some special management aspects of CAT, the objective of this review is to present a current overview and recommendations for the treatment of CAT.

Prevalence and factors associated with inappropriate dosing of apixaban and rivaroxaban in hospitalized older adults with atrial fibrillation: a cross-sectional study.

Atrial fibrillation (AF) is a common condition among older adults, requiring anticoagulation therapy to prevent thromboembolic events. Direct oral anticoagulants (DOACs) are now recommended as first-line therapy for this purpose. Apixaban and rivaroxaban are two direct-factor Xa inhibitors whose dosing is based on various factors (age, weight, creatinine, and creatinine clearance) that can affect the pharmacokinetics of the medication. This study aimed to evaluate factors associated with inappropriate dosing of apixaban or rivaroxaban based on the summary of product characteristics. A retrospective, single-center study included 777 hospitalizations of patients treated with apixaban or rivaroxaban for AF between 1 January 2018 and 31 December 2022. Primary endpoint assessed whether the dose of apixaban or rivaroxaban was within the summary of product characteristics used by European Medicine Agency (EMA). Inappropriate dosing of apixaban or rivaroxaban is noted for approximately 30% of hospitalizations mostly underdosing. Factors associated with the risk of inappropriate dosing were the presence of cognitive impairment [adjusted odds ratio (OR*) 1.65, 95% confidence interval (CI) 1.19-2.29, p value (p) = 0.002], weight per kilogram increase (OR* 1.03, 95% CI 1.01-1.04, p < 0.0001), and history of bleeding under apixaban or rivaroxaban (OR* 1.94, 95% CI 1.24-3.03, p = 0.003). This study highlighted the high prevalence of inappropriate apixaban or rivaroxaban doses in older adults, particularly underdosing, which increases the risk of thromboembolism.

Oral anticoagulation in heart failure complicated by atrial fibrillation: a nationwide routine data study

Abstract Background/Introduction Heart failure (HF) is frequently complicated by atrial fibrillation (AF). The co-occurrence of both conditions worsens the overall patient prognosis (1). To reduce the risk of thromboembolic complications, current guidelines highly recommend an oral anticoagulant (OAC) therapy in the majority of patients affected (2). Purpose Aim of this study was to evaluate whether a permanent OAC therapy in patients with HF and AF leads to favourable outcomes. Additional benefits of new oral anticoagulants (NOACs), compared to vitamin K antagonists (VKA), were further assessed. Methods Anonymous routine data of patients who were medically insured at the largest German health insurance provider and had a claims record for hospitalisation with the main diagnosis of HF and AF (2017-2019) were included. Admission due to HF in the previous year, incomplete medication data within 90 days after hospital stay as well as the diagnoses of congenital anomaly, transplantation, asthma, and age under 30 years were exclusion criteria. The endpoints of mortality and readmission rate for all-cause and stroke/intracranial bleeding (ICB) 91-365 days after the index hospitalisation were analysed. For this, information about the medications was taken from the pharmacy database. Kaplan-Meier survival curves and multivariable Cox regression models were used to evaluate the impact of medication on outcome. Adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated. Patient age, sex, and comorbidities were evaluated as independent factors, including all variables of the CHA2DS2-VASc score. Results We included n = 180,316 cases (see figure 1). The median age was 81 years (interquartile range of 76-86) with 55.6% of the patients being female. 96.81% had a CHA2DS2-VASc score of ≥ 2. We found OAC prescription in 80.6% (VKA: 21.7%; direct factor Xa inhibitors (FXaI): 60.0%; direct thrombin inhibitors (DTI): 3.4%). In 8,087 cases, more than one OAC was prescribed. The mortality rate was 19.1%, readmission rate was 29.9% and stroke/ICB occurred in 1.9% during the observed time span. As presented in figure 2, the risk of death was lower with any OAC (HR 0.77, 95% CI 0.75-0.79) but without significant differences in OAC type (VKA: HR 0.73, 95% CI 0.71-0.76; FXaI: HR 0.77, 95% CI 0.75-0.78; DTI: HR 0.71, 95% CI 0.66-0.77). The total readmission rate (HR 0.97, 95% CI 0.94-0.99) and readmission for stroke/ICB (HR 0.71, 95% CI 0.65-0.77) was likewise lower with OAC use. Conclusion(s) Routine data confirm the beneficial outcome of OAC therapy in patients with HF complicated by AF regarding mortality and readmission for all-cause as well as for stroke/ICB. No additional benefits were visible with the use of NOACs.Figure 1.Patient selection criteria.Figure 2.Kaplan-Meier survival (OAC).

Baseline demographic and clinical characteristics as predictors of adverse outcomes to improve management of patients with AF receiving edoxaban: a subanalysis of the ETNA-AF registry

Abstract Background/Introduction Atrial fibrillation (AF) is associated with substantial morbidity and mortality for patients, and significant burden for societal health and health economy. Even optimal oral anticoagulation and treatment of concomitant conditions leave an unacceptable remaining morbidity and mortality. Aim The purpose of this analysis was to identify clinical parameters associated with cardiovascular events in patients with AF receiving adequate anticoagulation. Methods The Global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF observational, non-interventional programme prospectively collects data on characteristics and clinical outcomes in patients treated with the direct oral factor Xa inhibitor edoxaban for stroke prevention in AF from Europe, Japan, and other Asian countries. A risk prediction model was built and evaluated for two dependent variables: composite endpoint 1, consisting of cardiovascular (CV) death, all stroke or systemic embolism or transient ischaemic attack (TIA), myocardial infarction (MI), and venous thromboembolism (VTE); and composite endpoint 2, consisting of CV death, all stroke, and MI. Independent variables used to identify predictors of the composite endpoints included the following parameters at baseline: age, history of any stroke/TIA, peripheral arterial disease (PAD), heart failure (HF), coronary artery disease (CAD), major or clinically relevant non-major gastrointestinal bleeding, chronic obstructive pulmonary disease, body mass index &amp;lt;18.5 kg/m2, weight, creatinine clearance (CrCl), history of valvular disease, history of diabetes mellitus, smoking history, age ≥85 years, and hepatic impairment. Multivariable Cox analysis with stepwise selection was used to identify baseline predictors of the composite endpoints. Results Overall, 26,580 edoxaban patients were included in the analysis. At baseline, 3034 (11.4%) patients were ≥85 years. Additional baseline demographics and clinical characteristics are reported in Table 1. All clinical variables were significant predictors (P &amp;lt;0.05) of both composite endpoints. Stronger predictors of composite endpoint 1 included history of any stroke/TIA, PAD, HF, higher weight, and lower CrCl (all P &amp;lt;0.0001; Figure 1). Most significant predictors of composite endpoint 2 included a history of ischaemic stroke, PAD, HF, and weight (P &amp;lt;0.0001; Figure 1). Conclusion A history of ischemic stroke, peripheral artery disease, heart failure, and weight identify patients with atrial fibrillation at risk of cardiovascular events on optimal current therapy. These patients may benefit from targeted interventions including early rhythm control and intensified, integrated management. Additional external validation will be performed to further the additive value of the analysis presented here.Table 1Figure 1

A meta-analysis of high-dose versus low-dose 4-factor prothrombin complex concentrate for reversal of factor Xa inhibitor-associated intracerebral hemorrhage

Abstract Background Four-factor prothrombin complex concentrate (4FPCC) are often used off-label for treating factor Xa inhibitor-associated major bleeding, including intracerebral hemorrhage (ICH). In addition to debate over 4FPCC’s effectiveness and safety compared with specific reversal agents, questions regarding the optimal 4FPCC dose remain. Purpose To evaluate the comparative effectiveness of high-dose versus low-dose 4FPCC for management of factor Xa inhibitor-associated ICH. Methods A systematic literature search of electronic databases (PubMed, Embase, and Cochrane) was conducted through January 31, 2023, to identify studies comparing high-dose versus low-dose 4FPCC for reversal of factor Xa inhibitors in individuals with an ICH. The outcomes of interest were hemostatic effectiveness (as defined by the individual study) and thromboembolism. Odds ratios (OR) and their corresponding 95% confidence intervals (CI) individual study comparisons of high- and low-dose 4FPCC were pooled using a random-effects model. Studies were stratified according to whether multivariable adjusted analyses were performed. Results Six studies with a total of 447 individuals (high-dose = 254, low-dose = 193) were included. Definition of high-dose 4FPCC included ≥ 30 IU/kg (n=1), ≥ 35 IU/kg (n=3), and 50 IU/kg (n=2). Definition of low-dose 4FPCC 25 IU/kg (n=2), &amp;lt; 30 IU/kg (n=1), and &amp;lt;35 IU/kg (n=3). The overall pooled proportion of hemostatic effectiveness for 4FPCC was 81.4% (95% CI 77.6 to 84.8%) with no evidence of a difference between those receiving high-dose versus low-dose 4FPCC (OR 1.36, 95% CI 0.57-3.28; Figure). In five studies, the pooled proportion of individuals who developed a thrombosis after receiving 4FPCC was 3.1% (95% CI 0 to 15.7%) with no evidence of a difference in odds between high-dose and low-dose (OR 1.23, 95% CI 0.56 to 2.72). Conclusion Evidence from mostly small single-center retrospective cohort studies suggests that using high-dose 4FPCC for reversal of factor Xa inhibitor-associated ICH is not associated with differences in the odds of hemostatic effectiveness or thrombosis when compared to the low-dose.Figure.Results of Meta-Analysis

Abstract 13192: Anti-Factor Xa Activity in Patients With Chronic Thromboembolic Pulmonary Disease With or Without Pulmonary Hypertension Treated With Factor Xa Inhibitors

Introduction and Hypothesis: Data on the efficacy and safety of factor Xa (FXa) inhibitors in chronic thromboembolic pulmonary disease (CTEPD) patients, especially in chronic thromboembolic pulmonary hypertension (CTEPH) patients, remain limited. Here, we aimed to evaluate the effect of FXa inhibitors by measuring anti-factor Xa activity (AXA) in both patients with CTEPD without pulmonary hypertension (PH) and CTEPH. Methods: Twenty-five CTEPD patients without PH and 52 CTEPH patients, treated with either of the FXa inhibitors were enrolled. AXA was measured by using HemosIL heparin calibrator. Blood samples were collected two times at the same day: immediately before the drug administration (trough) and 2-3 h after drug administration (peak). Results: In all 77 patients, median age was 66 (Interquartile range [IQR] 51–73) years, and 43% were male. In addition, 47% of the patients received rivaroxaban of 15 mg/day, 27% received apixaban of 10 mg/day, 14% received edoxaban of 60mg/day, and 12% received edoxaban of 30 mg/day. The median peak AXA of all 77 patients was 1.92 IU/mL and was comparable between CTEPD without PH and CTEPH patients. Significant difference of trough and peak AXA was shown among four different prescribed drugs (P &lt; .001 and P = .006, respectively). During the observational period of median 519 (IQR 364–1118) days, major and clinically relevant non-major bleeding occurred in six patients. ROC analysis to predict bleeding events revealed that the sensitivity and specificity of the cutoff point of a peak AXA of 2.1 IU/mL were 67% and 66%, respectively (AUC 0.66). The cumulative rate of major and clinically relevant non-major bleeding tended to be higher in patients with peak AXA ≥ 2.1 IU/mL than in patients with values below this point (p = .092, Figure). Conclusion: Measuring AXA could be a useful method to evaluate the effect of FXa inhibitors in CTEPD with or without PH patients.

Abstract 15557: A Retrospective Study of Clinical Pathways and Outcomes of Andexanet Alfa Administration for Reversal of Critical Bleeding or Urgent Surgery in Patients on Oral Direct Factor Xa Inhibitors

Introduction: Andexanet is FDA approved for reversal of life-threatening bleeding from factor Xa (FXa) inhibitors rivaroxaban and apixaban and off-label for urgent surgical reversal. Data are lacking on processes to ensure prompt andexanet dosing. Hypothesis: Presentation-to-andexanet time depends on clinical, demographic, and hospital factors. Goals: To identify factors impacting presentation-to-andexanet time and post-andexanet adverse outcomes. Methods: We retrospectively studied patients at a 23-hospital system who received andexanet from November 3, 2019, to March 4, 2023. Abstractors manually coded demographics, comorbidities, anticoagulant use, andexanet indication, and clinical pathway time stamps. The primary outcome was presentation-to-andexanet time. Secondary outcomes were post-andexanet major thromboembolism or bleeding, and in-hospital mortality. Results: 110 patients were analyzed (mean age 77.4 years, 71.3% White). Most patients were on lower dose FXa inhibitors without antiplatelets; 77% had at least 2 vascular comorbidities. Andexanet was used most for intracranial hemorrhage (ICH) (80%); 7% of doses were for urgent surgery (Table 1). Median presentation-to-andexanet time was 219 minutes. Linear regression showed non-ICH bleeding was associated with greater time to andexanet dose. More post-treatment thromboembolism or bleeding occurred at tertiary academic hospitals (p = 0.02). In-hospital mortality did not differ among hospital types (Table 2). Conclusions: In a retrospective study, a non-ICH site was associated with greater median time to andexanet dose. More post-andexanet adverse events occurred at tertiary hospitals.

Management of traumatic cervical epidural hematoma in patients on Xa-inhibitors: a case report and review of the literature

BackgroundCervical epidural hematoma (CEH) is defined as a collection of blood in the suprameningeal space. Mechanisms of this rare pathology include spontaneous, postsurgical, and traumatic as the main subtypes. This unique case of traumatic CEH represents an even smaller subset of these cases. Management varies by symptom presentation, mechanism of injury, and other contraindications.Case presentationThis case presents a 32 year old African American female on an oral anticoagulant sustaining traumatic cervical hematoma after a motor vehicle collision. Patient complained of neck, abdominal, and back pain. Imaging revealed a cervical spinal hematoma at the level of C3–C6. This case discusses the management of CEH for the general population and in the setting of anticoagulation.ConclusionManagement of each case of CEH must be carefully considered and tailored based on their symptom presentation and progression of disease. As the use of anticoagulation including factor Xa inhibitors becomes more prevalent, there is greater need to understand the detailed pathophysiological aspect of the injuries. Targeted reversal agents such as Prothrombin Concentrate can be used for conservative treatment. Adjunct testing such as thromboelastogram can be used to help guide management.

Abstract 11876: Impact of Online Continuing Medical Education on Advancing Physician Knowledge and Confidence Around Dual-Pathway Inhibition for Patients With Peripheral Artery Disease

Background: Patients with PAD are at risk for MACE and MALE. Antithrombotic therapy, including DPI can improve patient outcomes. Physicians who care for patients with PAD may require education to improve knowledge and confidence around employing newer treatments. Purpose: This study was conducted to determine if online CME could improve physician knowledge and confidence of advances in DPI for the treatment of patients with PAD. Methods: The educational program consisted of a 15-minute online video-based rapid-fire discussion between 2 experts that launched March 24, 2021-March 24, 2022. Data were collected from participants on March 24, 2022. Four multiple choice questions were used; 3 assessed knowledge and 1 determined confidence with Likert-type scale. Endpoints were assessed using a repeated-pair design with pre-/post-assessment. A paired samples t-test was conducted on overall average number of correct responses for physician knowledge, and a McNemar’s test was conducted at the question level (significance level, P &lt; .05) for confidence. Results: 855 physicians completed the pre-/post-assessment out of 3,825 total physician learners (22%). Physician specialties included general cardiology (28%), vascular cardiology (15%), vascular surgery (15%), other surgery (20%), and primary care (22%). Overall, significant improvements were seen in knowledge of medical treatment for PAD (P&lt;.001), data for the use of factor Xa inhibition to treat PAD (P&lt;.001), and confidence in selecting antithrombotic therapy (P&lt;.001) (Table). Gains in knowledge and confidence were highest amongst vascular specialists compared with non-vascular specialists (Table). Conclusion: This study demonstrates the effect of a 15-minute online video-based CME discussion between 2 expert faculty on knowledge and confidence among providers caring for patients with PAD related to advances in antithrombotic therapy. Continued gaps were identified for future educational targets.

Reversal of pre-injury factor-Xa inhibitors with prothrombin complex concentrates in patients following traumatic brain injury

IntroductionThere is substantial debate on the best method to reverse factor Xa-inhibitors in patients following traumatic brain injury (TBI). Prothrombin complex concentrates (PCC) have been used for this indication but their role has been questioned. This study reported failure rates with PCC in patients following TBI and as a secondary objective, compared 4-factor (4 F-PCC) and activated PCC (APCC). Material and methodsConsecutive patients with TBI on factor Xa-inhibitors admitted to one of two trauma centers were retrospectively identified. Patients with penetrating TBI, delays in PCC administration (>6 h), receipt of tranexamic acid, factor VIIa or no follow up CT-scan were excluded. The primary outcome was treatment failure defined as hematoma expansion > 20% from baseline for SDH, EDH or IPH, a new hematoma not present on the initial CT scan or any expansion of a SAH or IVH. Hematoma expansion was further categorized as symptomatic or asymptomatic, designated by a change in the motor GCS score, neurologic exam or change ≥ 3 in NIH Stroke Scale. Multi-variate analysis was performed. ResultsThere were 43 patients with a mean age of 77 ± 13 years with primarily mild TBI (95%) after a ground level fall (79%). The mean dose was 41 ± 12 units/kg. Sixty percent received 4 F-PCC and 40% APCC. The incidence of treatment failure was 28% (12/43). Of the 12 patients with hematoma expansion, only 3 were symptomatic (9.3%). Hematoma expansion with 4 F-PCC and APCC were similar (27% vs. 29%,p = .859). Only sex was associated with hematoma expansion on multivariate analysis [OR (95% CI) = 6.7 (1.1 – 40.9)]. ConclusionPCC was an effective option for factor Xa inhibitor reversal following TBI. The relationship between radiographic expansion and clinical expansion was poor.